Inhibiting Cif enzyme could be novel treatment for CF

Action Points

Note that researchers have identified an epoxide hydrolase enzyme, Cif, that may mediate some of the inflammatory effects of Pseudomonas aeruginosa infection in patients with cystic fibrosis.

These findings will lead to an analysis of Cif inhibitors as potential therapeutic agents.

Identification of a new class of bacterial enzymes that are key players in the chronic pulmonary inflammation characteristic of cystic fibrosis could lead to novel treatments for the disease, researchers say.

In a series of studies, they found that the opportunistic bacterial pathogen Pseudomonas aeruginosa promotes inflammation through secretion of the epoxide hydrolase enzyme CFTR inhibitory factor (Cif). This secretion sabotages the body's ability to make a key anti-inflammatory molecule known as pro-resolving lipid mediator, researchers wrote online in the Proceedings of the National Academy of Sciences.

"P. aeruginosa drives in the hyper-inflammatory cystic fibrosis lung, forming biofilms that are mechanically robust and resistant to clinically achievable levels of antibiotics. P. aeruginosa also persists in the airways by interfering with host defense via secreted bacterial virulence factors and small molecules," Jennifer Bomberger, PhD, of the University of Pittsburgh School of Medicine, and colleagues wrote.

Earlier research by the same group showed that P. aeruginosa secrete the Cif enzyme. Transcripts of the enzyme have been found in the sputum of patients with cystic fibrosis, but Cif's role in cystic fibrosis pathogenesis and the identify of host epoxide substrates were not known, the researchers wrote.

"We knew this enzyme was an epoxide hydrolase for several years, but we didn't know if it had any targets in the host," Bomberger told MedPage Today.

"In the cystic fibrosis lung, the concentration of lipoxin A4 is significantly reduced, suggesting that a failure to activate pro-resolving mechanisms contributes to excessive inflammation in the airways," the researchers wrote.

Using a combination of in vitro biochemistry approaches, the researchers found that Cif secreted by P. aeruginosa disrupts 15-epi LXA4 transcellular biosynthesis and function.

"In the airway, 15-epi LXA4 production is stimulated by the epithelial-derived eicosanoid 14,15-epoxyeicosatrienoic acid (14,15-EET)," they wrote. "Cif sabotaged the production of 15-epi LXA4 by rapidly hydrolyzing 14,15-EET into its cognate diol, eliminating a pro-resolving signal that potentially suppresses IL-8-driven neutrophil trans-epithelial migration in vitro."

Retrospective analysis of secretions from the lungs of cystic fibrosis patient supported this finding, showing Cif expression to be widespread and correlated with elevated IL-8, loss of 15-epi LXA4 and reduced pulmonary function.

"Taken together, our results provide evidence for a novel role of the bacterial epoxide hydrolase Cif in obstructing normal resolution pathways in the airway and promoting pulmonary inflammation in cystic fibrosis patients colonized with P.aeruginosa," the researchers wrote.

They concluded that Cif represents, "a key link between chronic infections and the damaging, hyper-inflammatory environment present in the cystic fibrosis airway," which may serve as a valuable biomarker for disease progression and treatment response.

The findings have important implications for the understanding of cystic fibrosis disease pathogenesis, and could potentially lead to novel treatment approaches, the researchers wrote.

Previous studies in pneumonia-model mice have found that therapies which increase levels of the pro-resolving lipid mediator reduce inflammatory response and promote clearance of P. aeruginosa.

Bomberger said therapies that directly inhibit the Cif enzyme could potentially prevent inflammation from occurring in the first place.

"We have identified Cif inhibitors, and we are now working on the chemistry and how to make them more bioavailable," she said. "In terms of inhibiting the enzyme, we have very promising compounds for doing that."

She added that the biggest hurdle will be getting these Cif inhibitors to their targets.

"Delivery is a consistent problem in cystic fibrosis," she said. "Getting any medication to where it needs to be in the lungs through the thickened mucus of the airways is a big challenge."

The research was funded by the National Institutes of Health, Gilead Sciences Research and a Munck-Pfefferkorn Award.

The researchers declared no relevant relationships with industry related to this study.

Accessibility Statement

At MedPage Today, we are committed to ensuring that individuals with disabilities can access all of the content offered by MedPage Today through our website and other properties. If you are having trouble accessing www.medpagetoday.com, MedPageToday's mobile apps, please email legal@ziffdavis.com for assistance. Please put "ADA Inquiry" in the subject line of your email.